Use of a specific cyclic amine derivative or the pharmaceutically acceptable salts thereof for the treatment or prevention of heart failure

ABSTRACT

The present invention provides the use in a pharmaceutical composition of a specific cyclic amine derivative, or its pharmaceutically acceptable salts, for the treatment or prevention of heart failure of any aetiology.

RELATED APPLICATIONS

[0001] The priority benefit of EP 02 016 602.1, filed Jul. 25, 2002 andU.S. Provisional Application No. 60/405,915, filed Aug. 26, 2002 arehereby claimed, both of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to the novel use of a cyclic aminederivative, namely cilobradine, or the pharmaceutically acceptable saltsthereof, for the treatment or prevention of heart failure of anyaetiology.

BACKGROUND OF THE INVENTION

[0003] Heart failure is a major world-wide public health problem and isthe only cardiac disorder that is increasing in incidence. In the UnitedStates alone, 5 million patients suffer from heart failure, with a newdiagnosis made in 0.5 million patients per year. Despite advances intherapy over the last decade, the annual number of hospitalisations hasincreased from 550 000 to 900 000 as a primary diagnosis, and from 1.7to 2.6 million as a primary or secondary diagnosis (J. Am. Pharm.

[0004] Assoc., vol. 41(5), pp. 672-681, 2001). Unless treated, heartfailure may lead to death. Hence, new approaches are warranted to treator prevent heart failure.

[0005] Although the terminology heart failure seems to be the mostaccepted terminology for describing this cardiac disorder, variousfurther equivalent terminologies can be found in the scientific, patentor medical literature as, for example, cardiac failure, insufficientcardiac output, cardiac insufficiency, cardiac collapse and cardiacsyncope.

[0006] Furthermore, though heart failure is invariably a chronic cardiacdisorder, often with an insidious onset, heart failure may be presentacutely or be punctuated by episodes of acute deterioration, so called“decompensated” heart failure. To describe these conditions also relatedto heart failure, further terminologies will commonly be found in thescientific, patent or medical literature such as, for example, chronicheart failure, acute heart failure, heart decompensation, cardiacdecompensation and cardial decompensation.

[0007] Lastly, as will be explained in the foregoing, as heart failurecan be caused by a dysfunctioning of the heart reflected by variousclinical presentations and sometimes subjected to further complications,further terminologies related to heart failure will also commonly befound in the scientific, patent or medical literature such as, forexample, myocardial failure, myocardial insufficiency, heart muscleinsufficiency, cardiac muscle insufficiency, heart muscle weakness,cardiac muscle weakness, systolic or left ventricular heart failure,diastolic heart failure, left or right sided heart failure,biventricular heart failure and congestive heart failure.

[0008] Hence, a distinction can be made between the systolic ordiastolic origin of the dysfunctioning. Commonly, heart failure is aconsequence of a progressive deterioration of myocardial contractilefunction, named systolic or left ventricular dysfunction. However,diastolic dysfunction is becoming increasingly recognised as animportant cause of heart failure too. This occurs when the heartchambers are unable to expand sufficiently during diastole (period ofheart relaxation in which the chambers fill with blood) and hence bloodvolume in the ventricles is inadequate. Whether systolic and/ordiastolic dysfunction is the basis of heart failure, cardiac output isdiminished. When additionally there is “damming” back of blood in thevenous system, congestion may ensue in the lungs (pulmonary oedema)and/or in the abdomen or peripheries (peripheral oedema). When bothoccur, the terminology congestive heart failure is often used.

[0009] In other respects, the distinction between left and right sidedheart failure can be applied to reflect the clinical presentation (i.e.pulmonary oedema indicative of left sided heart failure, whereas theprincipal symptom of right sided heart failure is fluid retention in theperipheries) or to denote the underlying cause. Right sided heartfailure is most commonly a consequence of left sided heart failure,although diseases of the lung (such as chronic obstructive pulmonarydisease), the right ventricle (e.g. right ventricular infarction) or thevasculature (primary or secondary pulmonary hypertension, the latter dueto conditions such as pulmonary embolism for example), may result inpredominate right sided heart failure.

[0010] According to the International Classification of Functioning,Disability and Health, lastly published by the World Health Organizationon 15 Nov. 2001 (ISBN 91 4 1545429) and accepted by 191 countries duringthe 54th World Health Assembly (Resolution WHA 54.21), heart failureoccurs when the heart function of pumping the blood in adequate orrequired amounts and pressure throughout the body is impaired.

[0011] As cardiac output is normally 5 litres/minute, although this canincrease five fold with heavy exercise, in essence, heart failure occurswhen the heart is unable to meet this demand.

[0012] As heart failure manifests itself in a variety of ways, at thetime of this patent application, the treatment or prevention of heartfailure comprises a combination of typical medications. Thesemedications are based upon the principles of promoting fluid excretionto lessen oedema and volume overload (e.g. various types of diuretics),vasodilatory drugs to reduce preload (i.e. atrial pressures) and/orafterload (i.e. pressure against which the heart has to beat), andinotropic drugs to increase contractility.

[0013] Vasodilatory drugs available at this time include AngiotensinConverting Enzyme (ACE) inhibitors, Angiotensin II Receptor blockers(ARBs) and nitrate venodilators. Inotropic drugs are usuallyadministered only in acute situations. Although cardiac glycosides suchas digoxin are sometimes prescribed for their inotropic properties,their use is more common in heart failure patients when atrialarrhythmias co-exist.

[0014] Recently, beta-blockers, which were once thought to becontra-indicated in heart failure due to their negative inotropic(decreased contractility) property, have been shown to be effective inthe treatment of heart failure. Meta-analyses of randomised controlledtrials have shown that, in addition to established background therapy ofACE inhibitors and diuretics with or without digoxin, a reduction of allcause mortality and cardiovascular morbidity is conferred bybeta-blockers such as carvedilol, metoprolol or bisoprolol (Brophy J. M.et al., Ann. Intern. Med. 2001, Vol. 134, pp. 550-560; Lechat P. et al.,Circ. 1998, pp. 1184-1191; Heidenreich P. A. et al., J. Am. Coll.Cardiol., 1997, Vol. 30, pp 27-34).

[0015] As heart failure progresses, heart failure treatment is alsousually not limited to one single therapy. Hence, add-on therapy use isdisclosed for carvedilol, for example, in WO 96/24348, for decreasingthe mortality of patients suffering from congestive heart failure. WO96/40258 discloses a combination therapy comprising an angiotensin 11antagonist and spironolactone, an aldosterone receptor antagonist, forthe treatment of hypertension, congestive heart disease, cirrhosis andascites. WO 00/02543 discloses a combination therapy comprising anangiotensin 11 antagonist (valsartan) and a calcium channel blocker(amlodipine or verapamil) for the treatment of several heart diseases,amongst which acute and chronic congestive heart diseases are cited.

[0016] However, as with all therapies, there are constraints to theiruse. For example, beta-blockers may be contra-indicated in patients withconcomitant diseases such as asthma, peripheral vascular disease anddecompensated heart failure. Certain drug classes may not be tolerateddue to unwanted side effects, e.g. cough with ACE inhibitors, fatigue,dizziness or impotence in association with beta-blockers, andhyponatraemia with diuretics. Furthermore, a slow and careful titrationperiod may be required upon drug initiation, as with beta-blockers,where if not performed, the initial negative effects on the heart'spumping action (negative inotropy) may result in drug intolerance anddeterioration in heart failure status.

[0017] Hence, to echo the statement set out at the beginning of thissection, despite the advances made by therapies established at thistime, there is still a need to reduce the unacceptable burden of heartfailure and new additional approaches to treatment and prevention ofdisease progression should be sought.

[0018] In searching for new therapies for heart failure, the underlyingpathophysiology of the failing heart needs to be considered. It has longbeen observed in the failing heart that heart rate and contractility areinitially increased in order to maintain cardiac performance. In thelong term, this response is ultimately damaging. It is, for example,acknowledged that increased heart rate is a risk factor for mortalityand morbidity with adverse consequences on vascular function,atherogenesis, myocardial ischaemia, myocardial energetics and leftventricular function. Chronic tachyarrhythmias are a cause of reversiblecardiomyopathy in humans and rapid atrial pacing is established as ananimal model of cardiomyopathy. In chronic heart failure, excessadrenergic stimulation signals adverse biological responses (includingincreased heart rate) via β1, β2 and α2 receptors in the myocardium.

[0019] In the failing heart, maintenance of adequate ventricularcontraction is sought, but occurs at the expense of oxygen and energyconsumption by the myocardium. Heart rate influences such energy demand,with increased heart rate requiring greater expenditure of energy. Thus,greater energetic efficiency could potentially result if heart rate werelowered in heart failure patients.

[0020] It thus follows that drugs which have the ability to reduce heartrate may be of benefit in the treatment or prevention of heart failure.For the treatment of cardiac insufficiency, a term also used to denoteheart failure, EP 0 471 388 (and its US counterpart U.S. Pat. No.5,516,773) suggests the use of a specific group of compounds derivedfrom the benzazepine basic chemical structure, and more specifically thecompound named zatebradine[1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-propane].

[0021] These benzazepine derivatives were firstly described in EP 0 065229, as well as their ability to reduce heart rate (bradycardic effect)by acting directly on the sinoatrial node, and their ability to reducethe oxygen requirement of the heart. Zatebradine is also known from WO01/78699 for the treatment and induction of the regression of idiopathichypertrophic cardiomyopathy (HCM), ischemic cardiomyopathy and valvularhypertrophic heart diseases.

[0022] The effects of the bradycardic agent zatebradine have beenstudied in a small number of patients with heart failure, also subjectto no therapy or atrial pacing, to induce a tachycardia (Shinke et al.,Jpn. Circ. Journal, 1999, Vol. 63, pp. 957-964) or in comparison to thebeta-blocker propranolol (Shinke et al. Abstract Circ., 1997, Vol.96,1-644).

[0023] In the former study, it was concluded by the authors that theoxygen saving effect of the bradycardia due to zatebradine treatmentcould be beneficial for the treatment of heart failure. In the latterstudy, the comparable heart rate reduction observed with zatebradine andthe beta-blocker had favourable effects compared to pre-treatment.However, it should be noted that under beta-blocker treatment overallcardiac efficiency was preserved, since the energy saving benefits ofheart rate reduction remedied the observed negative effect oncontractility. This, the authors proposed, might account for goodbeta-blockers tolerance and possible efficacy in heart failure.Zatebradine treatment however improved cardiac efficiency since heartrate reduction occurred, but with no accompanying adverse effect oncontractility.

[0024] It should be noted that these two studies are small and do notattempt to evaluate the benefits of chronic zatebradine administrationon the haemodynamic or clinical manifestations of heart failure.Furthermore, the relationships between heart rate reduction, leftventricular function and prognosis in heart failure are complex.However, there is a scientific rationale that improved cardiacenergetics secondary to heart rate reduction is an important concept inthe treatment and prevention of the progression of heart failure due tosystolic and/or diastolic dysfunction (Laperche et al., Heart 1999, Vol.81, pp. 336-341).

[0025] Another specific group of compounds derived from a basic cyclicamine chemical structure, have been shown to also have valuablepharmacological bradycardic properties. These compounds, the process fortheir preparation and pharmaceutical compositions containing them aredescribed in EP 0 224 794 and its US counterpart U.S. Pat. No.5,175,157.

[0026] One of these cyclic amine derivatives,3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one,and more particularly its S-(+) enantiomer named cilobradine[(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-(S)-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one],is also known from WO 01/78699 for the treatment and induction of theregression of idiopathic hypertrophic cardiomyopathy (HCM), ischemiccardiomyopathy and valvular hypertrophic heart diseases.

[0027] However, these cyclic amine derivatives, and more specificallycilobradine, have not been suggested for the treatment or prevention ofheart failure.

[0028] Scientific studies performed with zatebradine and cilobradine inorder to determine the mechanism of action of these bradycardicsubstances have shown that both zatebradine and cilobradine selectivelyblock hyperpolarisation activated, cAMP-modulated cation currentchannels (HCN) in cardiac conductive tissue, channels responsible forthe transmembrane current known as I_(f). It is through blockade of thiscurrent that zatebradine and cilobradine are assumed to produce theirspecific bradycardic effect.

[0029] However, HCN channels are widely distributed in the nervoussystem, and in the eye they mediate the current known as I_(h) . . . .The effect of zatebradine and cilobradine on the I_(h) channel has alsobeen investigated (Neuroscience, Vol. 59(2), pp. 363-373, 1994 forzatebradine, and British Journal of Pharmacology, Vol. 125, pp. 741-750,1998 for cilobradine). The results have suggested that although I_(h)can also be blocked by these compounds, the interaction with thechannels is somewhat different for both tissues. Since I_(h) has beendescribed in the different neurones of the visual signal processingsystem, the effect on I_(h) current has been suggested to be anexplanation for the side-effects (visual disturbances) seen by patientstreated with I_(f) blockers.

[0030] Further studies have been performed using electroretinogram (ERG)responses recorded from cat eyes and psychophysical measurementsconducted on volunteer human subjects, in normal conditions and afteradministration of zatebradine (Archives Italiennes de Biologie, vol.137, pp. 299-309, 1999, and Vision Research, vol. 39, pp. 1767-1774,1999). The results of these studies have shown that zatebradine reducesthe amplitude of the response to stimuli of frequency above 1 Hz, asshown by the ERG recordings. Furthermore, the measurement of theattenuation and phase characteristics of the first harmonic constructedby plotting the response amplitude and the phase as a function of thetemporal frequency of the stimulus in control conditions and afterintravenous injection or oral administration of zatebradine have shownthat the main effect of the I_(h) blocker zatebradine is to decrease theresponse amplitude to stimuli in the frequency range of 2 to 15 Herz, byintroducing a cut-off in the band-pass at about 2 Herz.

[0031] To confirm these assumptions, recent studies have been performedusing intraretinal and vitreal electroretinogram (ERG) recordings indark-adapted intact cat retina (Visual Neuroscience, vol. 18(3), pp.353-363, 2001). These studies compared the changes in the recovery phasefollowing the a- and b-waves induced by an exposure with bright flashesof diffuse white light, after intraretinal injections of substancesknown to block the responses of bipolar and horizontal cells, orsubstances known to block I_(h). The authors of this study haveconcluded that blockers of I_(h) reduce the recovery phase following thea-wave induced by the light exposure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032]FIG. 1 shows heart rate plotted against the applied dose ofzatebradine and: cilobradine.

[0033]FIG. 2 shows the attenuation and phase characteristics of the ERGresponse to sinusoidally modulated luminances evaluated by plotting theamplitude of the response to the light stimulus as a function of thetemporal frequency of the light stimulus.

[0034]FIG. 3 shows the attenuation and phase characteristics of the ERGresponse to sinusoidally modulated luminances evaluated by plotting theamplitude of the response to the light stimulus as a function of thetemporal frequency of the light stimulus.

[0035]FIG. 4 shows results in control conditions and in acute treatmentconditions with three different doses of cilobradine (triangles: 0.3 mgcilobradine/kg body weight; inverted triangles: 1 mg cilobradine/kg bodyweight; diamonds: 3 mg cilobradine/kg body weight).

[0036]FIG. 5 shows results in control condition and in acute treatmentcondition with a single dose of zatebradine of 3 mg/kg body weight.

[0037]FIG. 6 shows results of control condition and in chronic treatmentcondition with a single dose of cilobradine of 1 mg/kg body weight givenper day during 2 weeks.

[0038]FIG. 7 shows results in control conditions and in chronictreatment conditions with a double dose of zatebradine of 3 mg/kg bodyweight given per day during 2 weeks.

SUMMARY OF THE INVENTION

[0039] From the results of the recently published scientific studies onthe mechanism of action of bradycardic substances, which were discussedin the previous section, one would not expect an advantage ofcilobradine over zatebradine in the treatment of cardiac disorders suchas heart failure.

[0040] However, as shall be discussed below, it has surprisingly beenfound that cilobradine presents an advantage over zatebradine not onlyin terms of its pharmacologically longer duration of action and dosepotency, but more importantly in its cardioselectivity, resulting indecreased or absent visual side effects when compared to therapeuticdoses of zatebradine.

[0041] Hence, a first object of the present invention is thatcilobradine has intrinsically different pharmacological properties thanzatebradine, which permit full cardiac ion channel blockade with absentor diminished retinal effects. This unexpected cardioselective propertyrepresents a clear advantage for cilobradine over, for example,zatebradine, for the treatment of cardiac disorders such as heartfailure.

[0042] A further object of the present invention is that cilobradine iseffective for the treatment or prevention of heart failure of anyaetiology and thus, is able to reduce the mortality and morbidityassociated with heart failure of any aetiology.

[0043] Thus, the present invention is directed to the use ofcilobradine, or its pharmaceutically acceptable salts, for the treatmentor prevention of heart failure of any aetiology.

[0044] The present invention is also a method for the treatment orprevention of heart failure of any aetiology, by administration to apatient in need thereof of a pharmaceutical composition comprisingcilobradine, or its pharmaceutically acceptable salts, together with apharmaceutically suitable carrier.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0045] In accordance with one embodiment, the present invention providesfor a novel use of the cyclic amine derivative(+)-3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-(S)-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one,named cilobradine, or its pharmaceutically acceptable salts.

[0046] For the preparation of cilobradine or the pharmaceuticallyacceptable salts of cilobradine, reference is made to EP 0 224 794 andits US counterpart U.S. Pat. No. 5,175,157, which describes the chemicalsynthesis of these compounds.

[0047] In accordance with a further embodiment of the present invention,amongst the pharmaceutically acceptable salts of cilobradine describedin EP 0 224 794 and its US counterpart U.S. Pat. No. 5,175,157, thehydrochloride and hydrobromide salts of cilobradine are preferred.

[0048] More particularly, the present invention is directed to the useof cilobradine, or its pharmaceutically acceptable salts, for thepreparation of a pharmaceutical composition for the treatment orprevention of heart failure of any aetiology.

[0049] In accordance with a further embodiment, the present invention isdirected to the use of cilobradine, or its pharmaceutically acceptablesalts, for the preparation of a pharmaceutical composition for theprevention of heart failure of any aetiology.

[0050] In accordance with a further embodiment of the present invention,the treatment or prevention of heart failure may be assessed by theability of the compound or pharmaceutical composition in accordance withthe present invention to reduce the mortality and morbidity associatedwith heart failure of any aetiology.

[0051] In accordance with a further embodiment of the present invention,the treatment or prevention of heart failure also comprises thetreatment or prevention of cardiac insufficiency, cardiac failure, heartinsufficiency, myocardial failure, myocardial insufficiency, heartmuscle insufficiency, cardiac muscle insufficiency, insufficient cardiacoutput, heart muscle weakness, cardiac muscle weakness, cardiaccollapse, cardiac syncope, chronic heart failure, acute heart failure,heart decompensation, cardiac decompensation, cardial decompensation,diastolic heart failure, right sided heart failure, systolic heartfailure, left ventricular heart failure, left sided heart failure,biventricular heart failure and congestive heart failure.

[0052] In accordance with a further embodiment of the present invention,heart failure of any aetiology means heart failure diagnosed as aconsequence or complication of any other condition, disease or disordersuch as, for example, systolic dysfunction, diastolic dysfunction,ischaemic heart diseases, including myocardial infarction, rightventricular infarction and chronic ischaemia, coronary heart diseases,hypertension, primary pulmonary hypertension, secondary pulmonaryhypertension, pulmonary embolism, pulmonary arterial stenosis, chronicobstructive pulmonary disease, restrictive cardiomyopathies, dilatedcardiomyopathies due to infectious, toxic, metabolic, familial orunknown reasons, myocarditis, congenital anomalies, tachycardias andventricular hypertrophy secondary to genetic or valvular disorders suchas tricuspid valve insufficiency, mitral and/or aortic valve disorders,heart infarcts, thyroid diseases and anaemia.

[0053] In accordance with a further embodiment, for the treatment orprevention of heart failure, a combination of cilobradine, or itspharmaceutically acceptable salts, with other substances such as, forexample, diuretics, cardiac glycosides, ACE (Angiotensin ConvertingEnzyme) inhibitors, ARBs (Angiotensin Receptor Blockers), vasodilators,beta blockers and inotropes, present in the same pharmaceuticalcomposition, or given as separate therapies (so-called adjunctivetherapy), is also within the scope of the present invention.

[0054] In accordance with a further embodiment of the present invention,the pharmaceutical composition for use in accordance with the presentinvention, comprising cilobradine or its pharmaceutically acceptablesalts, alone or in combination with other heart failure therapiesincluding ACE inhibitors, ARBs, diuretics or cardiac glycosides, may beadministered to patients in any medically acceptable manner.

[0055] In accordance with a further embodiment of the present invention,the pharmaceutical composition for use in accordance with the presentinvention, comprising cilobradine or its pharmaceutically acceptablesalts, may be formulated as liquid formulation or lyophilised powder fororal or parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation is generally an aqueoussolution. Such formulation is especially suitable for oraladministration, but may also be used for parenteral administration orcontained in a metered dose inhaler or nebulizer for insufflation. Itmay be desirable to add excipients such as polyvinylpyrrolidone orhydroxycellulose to the composition.

[0056] In accordance with a further embodiment of the present invention,the liquid formulation may be administered directly per orally or filledinto a soft capsule.

[0057] Alternatively, the ingredients may be encapsulated, tableted orprepared in a syrup for oral administration. Pharmaceutically acceptablesolid or liquid carriers may be added to enhance or stabilise thecomposition, or to facilitate the preparation of the composition. Thecarrier may also include a sustained release material.

[0058] In accordance with a further embodiment of the present invention,the pharmaceutical compositions are prepared following the conventionaltechniques of pharmacy involving milling, mixing, granulating, andcompressing, when necessary, for tablet forms, or milling, mixing andfilling for capsule forms.

[0059] For the preparation of pharmaceutical compositions comprisingcilobradine or its pharmaceutically acceptable salts, reference is madein particular to EP 0 224 794 and its US counterpart U.S. Pat. No.5,175,157 and to WO 01/78699, which describe examples of injectable,oral liquid, tablet, capsule and suppository formulations of cilobradineor its pharmaceutically acceptable salts.

[0060] In accordance with a further embodiment of the present invention,the preferred galenical formulation is a tablet or liquid drinkingsolution, although capsule, suppository and injectable formulations ofthe active substance cilobradine or its pharmaceutically acceptablesalts are also comprised within the scope of the present invention.

[0061] In accordance with a further embodiment of the present invention,the pharmaceutical composition comprising the active compoundcilobradine or its pharmaceutically acceptable salts can be administeredto animals as well as humans.

[0062] In accordance with a further embodiment of the present invention,the pharmaceutical composition comprising the active compoundcilobradine or its pharmaceutically acceptable salts is preferablyadministered following a single or multiple stage daily applicationscheme.

[0063] In accordance with a further embodiment of the present invention,when administered for the treatment or prevention of heart failure,preferably a dose of 0.01 to 20 mg/kg body weight of the activesubstance cilobradine or its pharmaceutically acceptable salts is used,and this in one or more applications per day. Within this range, thefollowing dose ranges are further preferred: 0.05 to 5 mg/kg bodyweight, 0.1 to 2.5 mg/kg body weight, 0.1 to 1 mg/kg body weight, and0.1 to 0.75 mg/kg body weight.

[0064] The invention will now be described in more detail with referenceto the following experiments.

[0065] As already mentioned above, previous studies (published inArchives Italiennes de Biologie, vol. 137, pp. 299-309, 1999, and VisionResearch, vol. 39, pp. 1767-1774, 1999) have established an experimentalanimal model to evaluate the side-effects (visual disturbances) seen bypatients treated with bradycardic agents, such as zatebradine. Thecontent of these references, and more particularly the experimentalparts described therein, are herein incorporated by reference.

[0066] These studies were based on a measurement of theelectroretinogram (ERG) responses recorded from cat eyes, in normalconditions and after administration of zatebradine.

[0067] In the following experiment, the same experiment was performedusing cilobradine, and the results compared to the results obtained withzatebradine.

[0068] In order to compare the visual side-effect of both compounds inconditions in which the drugs are pharmacologically the most effectivein these experiments, as for example in the reduction of heart rate, adose of 0.75 mg/kg body weight was chosen for cilobradine and a dose of2.5 mg/kg body weight was chosen for zatebradine. This selection of thedose is based on the result shown in FIG. 1, wherein the reduction ofheart rate is plotted against the applied dose of the drug (opencircles: zatebradine; filled circles: cilobradine). As can be seen fromFIG. 1, at a dose of 2.5 mg/kg body weight, a reduction of about 44% ofthe heart rate is obtained with zatebradine (maximum effect), and at adose of 0.75 mg/kg body weight, a reduction of about 75% of the heartrate is obtained with cilobradine (also maximum effect). Therefore, bychoosing these doses, it can already be assumed that the pharmacologicaleffect on heart rate of cilobradine is better than the pharmacologicaleffect of zatebradine.

[0069] In a similar experiment than the experiment performed by Garginiet al. (published in Vision Research, vol. 39, pp. 1767-1774, 1999), theattenuation and phase characteristics of the ERG response tosinusoidally modulated luminances was evaluated by plotting theamplitude of the response to the light stimulus as a function of thetemporal frequency of the light stimulus. The result of this experimentis shown in FIG. 2, wherein the open circles are the control responses(no active substance injected), the filled circles are the responses 15minutes after treatment with a dose of zatebradine of 2.5 mg/kg bodyweight (i.v. injection), and the triangles are the responses measured 5hours after the injection of zatebradine.

[0070] The results confirm the results already published by Gargini etal. (Vision Research, vol. 39, pp.1767-1774, 1999) that, at this dose,zatebradine reduces the amplitude of the response to stimuli offrequency above 1 Hz and shift the corresponding phase lags, as shown bythe ERG recordings. The measurements performed after 5 hours confirmthat the visual response is back to normal after 5 hours, and that theexperiment is non-destructive for the system.

[0071]FIG. 3 shows the results of the same experiment performed afterinjection of 0.75 mg/kg body weight of cilobradine, in the sameconditions. As is clear from the result, no visual effect can bedetected with cilobradine when injected in a fully heart rate reductioneffective dose.

[0072] We conclude from these results that a dose of cilobradine whichproduces a saturation effect on the heart rate has negligibleconsequences on the visual response. This evidences the advantage ofcilobradine over zatebradine to produce a pharmacological effect withless side-effect, and thus its superiority for the treatment of heartfailure.

[0073] A further similar experiment was performed in order to comparethe visual side-effect of cilobradine and zatebradine in conditionswhere the drugs are pharmacologically effective in reducing heart rate.The aim of this experiment was to compare the visual side-effect of bothdrugs in another experimental animal model, namely on the retinal systemof the rat. Furthermore, the aim of this experiment was also to comparethe visual side-effect of both drugs in acute and in chronic (over twoweeks) drug treatment conditions.

[0074] The principle of this experiment is again the same as theprinciple of the experiment performed by Gargini et al. and published inVision research, vol. 39, pp. 1767-1774, 1999).

[0075] Hence, this experiment was based on a measurement of theelectroretinogram (ERG) responses recorded from anesthetized pigmentedrats as a function of the temporal frequency of an applied oscillatinglight stimulus. The results of the experiment are visualized by plottingthe measurement of the first amplitude of the Fourier transform of theERG as a function of the applied stimulus frequency (oscillating lightstimulus of high luminance and contrast).

[0076] FIGS. 4 to 7 show the results of the experiment in differenttreatment conditions.

[0077]FIG. 4 shows the results of the experiment in control conditions(squares and circles) and in acute treatment conditions with threedifferent doses of cilobradine (triangles: 0.3 mg cilobradine/kg bodyweight; inverted triangles: 1 mg cilobradine/kg body weight; diamonds: 3mg cilobradine/kg body weight). The ERG measurements were made 30minutes after injection of the drug. The measured heart rate frequencywas: Control 400 beats per min. Cilobradine treatment 0.3 mg/kg 364beats per min. Cilobradine treatment 1 mg/kg 316 beats per min.Cilobradine treatment 3 mg/kg 270 beats per min.

[0078]FIG. 5 shows the results of the experiment in control condition(squares and circles) and in acute treatment condition with a singledose of zatebradine of 3 mg/kg body weight (circles). The ERGmeasurement was made 30 minutes after injection of the drug. Themeasured heart rate frequency was: Control 428 beats per min.Zatebradine treatment 3 mg/kg 333 beats per min.

[0079]FIG. 6 shows the results of the experiment in control condition(squares) and in chronic treatment condition with a single dose ofcilobradine of 1 mg/kg body weight given per day during 2 weeks(circles). The ERG measurement was made after the 2 weeks treatment. Themeasured heart rate frequency was: Control 400 beats per min.Cilobradine treatment 1 mg/kg 260 beats per min.

[0080]FIG. 7 shows the results of the experiment in control conditions(circles) and in chronic treatment conditions with a double dose ofzatebradine of 3 mg/kg body weight given per day during 2 weeks(squares). The ERG measurement was made after the 2 weeks treatment. Themeasured heart rate frequency was: Control 350 beats per min.Cilobradine treatment 1 mg/kg 285 beats per min.

[0081] From this experiment, it can be concluded that in acute treatment(results of FIGS. 4 and 5), at doses for which both drugs are effectivein reducing the heart rate (as confirmed by the values of the measuredheart rate frequency), no effect on the ERG can be detected withcilobradine, whereas a reduction of the amplitude of the response tostimuli of frequency above 1 Hz and a shift of the corresponding phaselags is observed with zatebradine.

[0082] Furthermore, the same conclusions can be made from the resultsobtained with chronic treatment over two weeks, as can be seen whencomparing the results of FIGS. 6 and 7.

[0083] This experiment performed with rats confirms the resultspreviously observed in cats that a dose of cilobradine effective forreducing the heart rate has negligible consequences on the visualresponse. This also demonstrates again the advantage of cilobradine overzatebradine to produce a pharmacological effect with less side-effect,and thus its superiority for the treatment of heart failure.

[0084] This experiment further demonstrates that cilobradine iseffective in reducing heart rate without visual side-effects, and thusits suitability in the acute treatment as well as in the chronictreatment of heart failure.

[0085] The invention will now also be described in more detail withreference to the following examples of pharmaceutical dosageformulations.

[0086] Hence, pharmaceutical formulations for medical use in humans havebeen prepared containing between 0.10 and 5 mg of active substance. Morespecifically, oral tablet formulations to be used as single or multipledose in a daily application scheme, and containing 0.25 mg, 0.5 mg, 1 mgor 2 mg active substance, have been prepared as described in thefollowing formulation examples of film coated tablets. Example 1 Example2 Example 3 Example 4 0.25 mg Dosis 0.5 mg Dosis 1 mg Dosis 2 mg Dosismg/Film mg/Film mg/Film mg/Film Coated Tablet Coated Tablet CoatedTablet Coated Tablet Core: Cilobradine 0.27 0.54 1.08 2.16 LactoseMonohydrat 56.42 56.15 82.28 164.56 (Tablettose) Microcrystalline 27.4527.45 40.38 80.76 Cellulose, Type 101 Na- 0.43 0.43 0.63 1.26Carboxymethylcellulose (Ac-Di-Sol) Magnesiumstearate, 0.43 0.43 0.631.26 (vegetal origin) Weight of Tablet Core: 85.00 85.00 125.00 250.00Coating: Hypromellose (Methocel 1.50 1.50 2.00 3.00 E5 Premium) Macrogol400 0.15 0.15 0.20 0.30 Titaniumdioxide 0.75 0.75 1.00 1.50 Talkum 0.600.60 0.80 1.20 Weight of Film Coated 88.00 88.00 129.00 256.00 Tablet:

[0087] These tablets may be used for the treatment or prevention ofheart failure as defined in the present invention.

What is claimed is:
 1. A method for the treatment or prevention of heartfailure, which comprises the administration to a patient in need thereofof a pharmaceutical composition comprising cilobradine or apharmaceutically acceptable salt thereof, together with apharmaceutically suitable carrier.
 2. The method of claim 1 for theprevention of heart failure.
 3. The method of claim 1 for the treatmentof heart failure.
 4. The method of claim 1 wherein the galenicalformulation of the pharmaceutical composition is a tablet, a drinkingsolution, a capsule, a suppository or an injectable formulation.
 5. Themethod of claim 4 wherein the galenical formulation of thepharmaceutical composition is a tablet.
 6. The method of claim 4 whereinthe galenical formulation of the pharmaceutical composition is adrinking solution.
 7. The method of claim 1 wherein the pharmaceuticalcomposition is administered following a single or multiple stage dailyapplication scheme.
 8. The method of claim 7 wherein the administereddose of cilobradine or its pharmaceutically acceptable salt is between0.01 and 20 mg/kg body weight.
 9. The method of claim 7 wherein theadministered dose of cilobradine or its pharmaceutically acceptable saltis between 0.05 and 5 mg/kg body weight.
 10. The method of claim 7wherein the administered dose of cilobradine or its pharmaceuticallyacceptable salt is between 0.1 and 2.5 mg/kg body weight.
 11. The methodaccording to claim 7 wherein the administered dose of cilobradine or itspharmaceutically acceptable salt is between 0.1 and 1 mg/kg body weight.12. The method of claim 7 wherein the administered dose of cilobradineor its pharmaceutically acceptable salt is between 0.1 and 0.75 mg/kgbody weight.
 13. The method of claim 1 wherein the treatment orprevention of heart failure is performed in combination with othertherapeutic agents for the treatment or prevention of heart failure. 14.The method of claim 13 wherein said therapuuetic agents includediuretics, cardiac glycosides, ACE inhibitors, ARBs, vasodilators, betablockers or inotropes.